Intra‐ and inter‐allelic ordering of T cell receptor β chain gene assembly

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Abstract
Allelic exclusion at the TCRβ locus mandates that gene assembly be regulated in a manner that permits feedback inhibition of further complete TCRβ rearrangements upon pre-TCR expression. Here we show that assembly of TCRβ chain genes from Vβ, Dβ and Jβ gene segments is intra-allelically ordered, proceeding primarily through DJβ, and not VDβ, intermediates. This ensures that Vβ to DJβ rearrangement, which can be feedback inhibited, is the final step in the assembly process. A newly assembled VDJβ rearrangement must be tested to determine if it is in-frame before Vβ to DJβ rearrangement is permitted on the alternate allele. This inter-allelic ordering may occur through a general inefficiency of Vβ to DJβ rearrangement and/or through static differences in accessibility of the two TCRβ alleles. However, we find that within the regulatory context of allelic exclusion, Vβ to DJβ rearrangement proceeds to completion on both alleles. Furthermore, all possible VDJβ rearrangements are not completed on one allele before Vβ to DJβ rearrangement is initiated on the alternate allele. Together, these data support a dynamic model of inter-allelic accessibility that permits the ordered and efficient assembly of complete variable region genes on both TCRβ alleles during T cell development.